This invention relates to new methods of using 5-fluoro-2-methyl-1-[[4-(methylthio)phenyl]methylene]-1H-indene-3-acetic acid or a therapeutically acceptable salt thereof with an organic or inorganic base for the treatment of complications associated with diabetes mellitus.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy and cataracts. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators, see J. H. Kinoshita et al., Biochem. Biophys. Acta, 158, 472 (1968) and references cited therein, have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6, 531 (1970).
5-Fluoro-2-methyl-1-[[4-(methylthio)phenyl]methylene]-1H-indene-3-acetic acid and its preparation are described by T.-Y. Shen et al., U.S. Pat. No. 3,654,349, issued Apr. 4, 1972 and D. F. Hinkley and J. B. Conn, U.S. Pat. No. 3,647,858, issued Mar. 7, 1972. 5-Fluoro-2-methyl-1-[[4-(methylthio)phenyl]-methylene]-1H-indene-3-acetic acid has anti-inflammatory, anti-pyretic and analgesic activity, D. E. Duggan et al., Biochem. Pharm., 27, 2311 (1978).
Surprisingly, 5-fluoro-2-methyl-1-[[4-(methylthio)phenyl]-methylene]-1H-indene-3-acetic acid or its therapeutically acceptable salt thereof with an organic or inorganic base, now has been found to be a potent inhibitor of lens aldose reductase. This new found property renders 5-fluoro-2-methyl-1-[[4-(methylthio)phenyl]methylene]-1H-indene-3-acetic acid, or a salt thereof, useful for the treatment of diabetic complications.